Process for preparing taxane derivatives

ABSTRACT

Method of preparing taxane derivatives of general formula (I) by esterification of protected baccatine III or 10-deacetyl-baccatine III by means of an acid of general formula (VII), deprotection of the side chain and elimination of the hydroxy function protection groupings. In general formulae (I) and (VII): Ar stands for aryl, R is hydrogen or acetyl, R 1  is benzoyl or R 2  --O--CO-- in which R 2  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl, and R 3  is hydrogen, alkoxy, optionally substituted aryl. ##STR1##

DESCRIPTION OF THE INVENTION

This application is a 35 U.S.C. 371 National Stage filing ofPCT/FR93/00968 published as WO 94/07878 on Apr. 14, 1994.

The present invention relates to a new process for preparing taxanederivatives of general formula: ##STR2## which possess noteworthyantileukaemic and antitumor properties.

In the general formula (I): R represents a hydrogen atom or an acetylradical, R₁ represents a benzoyl radical or a radical R₂ --O--CO-- inwhich R₂ represents an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, phenyl or nitrogenous heterocyclic radical,and Ar represents an aryl radical.

More especially, R represents a hydrogen atom or an acetyl radical andR₁ represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents:

an unbranched or branched alkyl radical containing 1 to 8 carbon atoms,an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 10 carbon atoms, these radicalsbeing optionally substituted with one or more substituents chosen fromhalogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinylradicals (optionally substituted at position 4 with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains i to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl, cyano or carboxyl radicals or alkyloxycarbonylradicals in which the alkyl portion contains 1 to 4 carbon atoms,

or a phenyl radical optionally substituted with one or more atoms orradicals chosen from alkyl radicals containing 1 to 4 carbon atoms oralkyloxy radicals containing 1 to 4 carbon atoms,

or a saturated or unsaturated 5- or 6-membered nitrogenous heterocyclicradical optionally substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms, on the understanding that thecycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionallysubstituted with one or more alkyl radicals containing 1 to 4 carbonatoms, and Ar represents a phenyl or α- or β-naphthyl radical optionallysubstituted with one or more atoms or radicals chosen from halogen(fluorine, chlorine, bromine, iodine) atoms and alkyl, alkenyl, alkynyl,aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl,hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano and trifluoromethylradicals, on the understanding that the alkyl radicals and alkylportions of the other radicals contain 1 to 4 carbon atoms, and that thealkenyl and alkynyl radicals contain 3 to 8 carbon atoms and the arylradicals are phenyl or α- or β-naphthyl radicals.

Of very special importance are the products of general formula (I) inwhich R represents a hydrogen atom or an acetyl radical, R₁ represents abenzoyl or t-butoxycarbonylamino radical and Ar represents a phenylradical.

The products of general formula (I) in which R₁ represents a benzoylradical correspond to taxol and to 10-deacetyltaxol, and the products ofgeneral formula (I) in which R₁ represents a t-butoxycarbonyl radicalcorrespond to those which form the subject of European Patent 0,253,738.

According to the process which is described in International ApplicationPCT W0 92/09,589, the derivatives of general formula (I) may be obtainedby:

condensation of an oxazolidine derivative of general formula: ##STR3##in which Ar is defined as above, Boc represents a t-butoxycarbonylradical and R'₂ and R'₃, which may be identical or different, representan alkyl radical containing 1 to 4 carbon atoms optionally substitutedwith one or more aryl radicals, or an aryl radical, or alternatively R'₂and R'₃, together with the carbon atom to which they are linked, form a4- to 7-membered ring, with protected 10-deacetylbaccatin III orbaccatin III of general formula: ##STR4## in which G₁ represents a groupprotecting the hydroxyl function and G₂ represents an acetyl radical ora group protecting the hydroxyl function, to obtain a product of generalformula: ##STR5## in which Ar, R'₂, R'₃, G₁, G₂ and Boc are defined asabove,

treatment of the product of general formula (IV) in an acid medium underconditions which have no effect on G₁ and G₂, to obtain the product ofgeneral formula: ##STR6## in which Ar, G₁ and G₂ are defined as above,treatment of the product of general formula (V) with a suitable reagentfor introducing a benzoyl radical or radical R₂ --O--CO--, to obtain aproduct of general formula: ##STR7## in which Ar, R₁, G₁ and G₂ aredefined as above, and replacement of the protective groups G₁ and G₂ ofthe product of general formula (VI) by hydrogen atoms to obtain theproduct of general formula (I).

It has now been found, and this forms the subject of the presentinvention, that the products of general formula (I) may be obtained by:

condensation of an acid of general formula: ##STR8## in which Ar and R₁are defined as above and R₃ represents a hydrogen atom or an alkoxyradical containing 1 to 4 carbon atoms or an optionally substituted arylradical, or of a derivative of this acid, with baccatin III or10-deacetylbaccatin III of general formula (III) in which G₁ representsa group protecting the hydroxyl function and G₂ represents an acetylradical or a group protecting the hydroxyl function, to obtain a productof general formula: ##STR9## in which Ar, R₁, R₃, G₁ and G₂ are definedas above, deprotection of the side chain and, where appropriate, of thehydroxyl functions protected by G₁ and G₂ to obtain a product of generalformula: ##STR10## in which Ar and R₁ are defined as above, G'₁represents a hydrogen atom or a group protecting the hydroxyl functionand G'₂ represents a hydrogen atom or an acetyl radical or a groupprotecting the hydroxyl function, and then

where appropriate, replacement of the protective groups G'₁ and, whereappropriate, G'₂ of the product of general formula (IX) by hydrogenatoms to obtain a product of general formula (I).

According to the invention, the esterification of the product of generalformula (III) is performed by means of an acid of general formula (VII),optionally in the form of an anhydride or in the form of a halide ormixed anhydride.

It is preferable to use an acid of general formula (VII), or itsactivated derivatives, in which R₃ represents a hydrogen atom or analkoxy radical containing 1 to 4 carbon atoms or a phenyl radicaloptionally substituted with one or more electron-donating radicalschosen more especially from the group comprising alkoxy radicalscontaining 1 to 4 carbon atoms.

The esterification by means of an acid of general formula (VII) may beperformed in the presence of a condensing agent, for instance acarbodiimide such as dicyclohexylcarbodiimide or a reactive carbonatesuch as di-2-pyridyl carbonate, and an activating agent, for instance anaminopyridine such as 4-(dimethylamino)-pyridine or4-pyrrolidinopyridine, working in an organic solvent chosen from etherssuch as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether ordioxane, ketones such as methyl isobutyl ketone, esters such as ethylacetate, isopropyl acetate or n-butyl acetate, nitriles suchacetonitrile, aliphatic hydrocarbons such as pentans, hexane or heptane,halogenated aliphatic hydrocarbons such as dichloromethane or1,2-dichloroethane or aromatic hydrocarbons such as benzene, toluene,xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at atemperature of between -10° and 90° C. It is especially advantageous toperform the esterification working in an aromatic solvent at atemperature in the region of 20° C.

The esterification may also be carried out using the acid of generalformula (VII) in the form of an anhydride of formula: ##STR11## in whichAr, R₁ and R₃ are defined as above, in the presence of an activatingagent, for instance an aminopyridine such as 4-(dimethylamino)pyridine,working in an organic solvent chosen from ethers such astetrahydrofuran, diisopropyl ether, methyl t-butyl ether or dioxane,ketones such as methyl isobutyl ketone, esters such as ethyl acetate,isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile,aliphatic hydrocarbons such as pentane, hexane or heptane, halogenatedaliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane oraromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene,isopropylbenzene or chlorobenzene, at a temperature of between 0° and90° C.

The esterification may also be carried out using the acid of generalformula (VII) in the form of a halide or in the form of a mixedanhydride of general formula: ##STR12## in which Ar, R₁ and R₃ aredefined as above and X represents a halogen atom or an acyloxy oraroyloxy radical, optionally prepared in situ, in the presence of a basewhich is preferably a nitrogenous organic base, for instance a tertiaryaliphatic amine such as triethylamine, pyridine, an aminopyridine suchas 4-(dimethylamino)pyridine or 4-pyrrolidinopyridine, working in aninert organic solvent chosen from ethers such as tetrahydrofuran,diisopropyl ether, methyl t-butyl ether or dioxane, esters such as ethylacetate, isopropyl acetate or n-butyl acetate, nitriles such asacetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane,halogenated aliphatic hydrocarbons such as dichloromethane or1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene,xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at atemperature of between 10° and 80° C., and preferably in the region of20° C.

It is preferable to use an activated derivative of general formula (XI)in which X represents a halogen atom or an acyloxy radical containing 1to 5 carbon atoms or an aroyloxy radical in which the aryl portion is aphenyl radical optionally substituted with 1 to 5 identical or differentatoms or radicals chosen from halogen (chlorine, bromine) atoms andnitro, methyl or methoxy radicals.

The deprotection of the side chain may be performed in the presence ofan inorganic acid (hydrochloric acid, sulphuric acid) or organic acid(acetic acid, methanesulphonic acid, trifluoromethane-sulphonic orp-toluenesulphonic acid) used alone or mixed, working in an organicsolvent chosen from alcohols (methanol, ethanol, propanol, isopropanol),ethers (tetrahydrofuran, diisopropyl ether, methyl t-butyl ether),esters (ethyl acetate, isopropyl acetate, n-butyl acetate), aliphatichydrocarbons (pentane, hexane, heptane), halogenated aliphatichydrocarbons (dichloromethane, 1,2-dichloroethane), aromatichydrocarbons (benzene, toluene, xylenes) and nitriles (acetonitrile), ata temperature of between -10° and 60° C., and preferably between 15° and30° C. The inorganic or organic acid may be used in a catalytic orstoichiometric amount or in excess.

The deprotection may also be carried out under oxidizing conditionsusing, for example, ammonium cerium IV nitrate in an acetonitrile/watermixture or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in water.

The deprotection may also be carried out under reducing conditions, forexample by hydrogenolysis in the presence of a catalyst.

The protective groups G₁ and G₂ are preferably2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonylradicals or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl ortriarylsilyl radicals in which the alkyl portions contain 1 to 4 carbonatoms and the aryl portions are preferably phenyl radicals.

Replacement of the protective groups G₁ and, where appropriate, G₂representing a silyl radical by hydrogen atoms may be performedsimultaneously with deprotection of the side chain.

Replacement of the protective groups G₁ and, where appropriate, G₂representing a 2,2,2-trichloro-ethoxycarbonyl or2-(2-trichloromethylpropoxy)carbonyl radical is performed with zinc,optionally in combination with copper, in the presence of acetic acid ata temperature of between 20° and 60° C., or by means of an inorganic ororganic acid such as hydrochloric acid or acetic acid dissolved in analiphatic alcohol containing 1 to 3 carbon atoms or in an aliphaticester such as ethyl acetate, isopropyl acetate or n-butyl acetate, inthe presence of zinc optionally in combination with copper.

This replacement may also be performed by electrolytic reduction.

The acid of general formula (VII) may be obtained by saponification in abasic medium of an ester of general formula: ##STR13## in which Ar, R₁and R₃ are defined as above and R₄ represents an alkyl radicalcontaining 1 to 4 carbon atoms optionally substituted with a phenylradical.

In general, the saponification is performed by means of an inorganicbase such as an alkali metal hydroxide (lithium, potassium, sodiumhydroxide) or an alkali metal carbonate or bicarbonate (sodiumbicarbonate, potassium carbonate or bicarbonate), in anaqueous-alcoholic medium such as a methanol/water mixture at atemperature of between 10° and 40° C., and preferably in the region of20° C.

The ester of general formula (XII) may be obtained by the action of analdehyde of general formula:

    R.sub.3 --CHO                                              (XIII)

in which R₃ is defined as above, optionally in the form of a dialkylacetal or an enol alkyl ether or an orthoformate of general formula:

    HC(OR.sub.3).sub.3                                         (XIV)

in which R₃ is defined as above, on a phenylisoserine derivative ofgeneral formula: ##STR14## in which Ar, R₁ and R₄ are defined as above,preferably in the 2R,3S form, working in an inert organic solvent in thepresence of a strong inorganic acid such as sulphuric acid or strongorganic acid such as p-toluenesulphonic acid, optionally in the form ofa pyridinium salt, at a temperature between 0° C. and the boiling pointof the reaction mixture. Solvents which are especially suitable arearomatic hydrocarbons.

The phenylisoserine derivative of general formula (XV) may be obtainedby acylation of a phenylisoserine derivative of general formula:##STR15## in which Ar and R₄ are defined as above.

The acylation is performed by the action of benzoyl chloride or areactive derivative of general formula:

    R.sub.2 --O--CO--Y                                         (XVII)

in which R₂ is as defined above and Y represents a halogen (fluorine,chlorine) atom or a residue --O--R₂ or --O--CO--O--R₂ working in anorganic solvent, for instance an aliphatic ester such as ethyl acetateor a halogenated aliphatic hydrocarbon such as dichloromethane, in thepresence of an inorganic or organic base such as sodium bicarbonate. Ingeneral, the reaction is performed at a temperature of between 0° and50° C., and preferably in the region of 20° C.

The product of general formula (XVI) may be prepared under theconditions described in International Application PCT WO 92/09,589.

The anhydride of general formula (X) may be obtained by reacting adehydrating agent such as dicyclohexylcarbodiimide with the acid ofgeneral formula (VII), working in an organic solvent chosen from etherssuch as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether ordioxane, ketones such as methyl isobutyl ketone, esters such as ethylacetate, isopropyl acetate or n-butyl acetate, nitriles such asacetonitrile, aliphatic hydrocarbons such as pentans, hexane or heptane,halogenated aliphatic hydrocarbons such as dichloromethane or1,2-dichloroethane or aromatic hydrocarbons such as benzene, toluene,xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at atemperature of between 0° and 30° C.

The activated acid of general formula (XI) may be obtained by the actionof a sulphuryl halide, preferably the chloride, or a product of generalformula:

    R.sub.5 --CO--Z                                            (XVIII)

in which R₅ represents an alkyl radical containing 1 to 4 carbon atomsor a phenyl radical optionally substituted with 1 to 5 identical ordifferent atoms or radicals chosen from halogen atoms and nitro, methyland methoxy radicals and Z represents a halogen atom, preferably achlorine atom, on an acid of general formula (VII), working in asuitable organic solvent such as tetrahydrofuran in the presence of anorganic base, for instance a tertiary amine such as triethylamine, at atemperature of between 0° and 30° C.

The process according to the present invention is especially useful forpreparing the products of general formula (I) in which R represents ahydrogen atom or an acetyl radical, R₁ represents a benzoyl ort-butoxycarbonyl radical and Ar represents an optionally substitutedphenyl radical.

EXAMPLES

The examples which follow illustrate the present invention.

EXAMPLE 1

A solution of 10.0 g of methyl (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 0.25 g ofpyridinium p-toluenesulphonate in 200 cm³ of toluene is dehydrated bydistilling off 20 cm³ of solvent. 6.34 cm³ of p-methoxybenzaldehydedimethyl acetal are added in the course of 5 minutes to the reactionmixture heated to boiling. During the addition, 50 cm³ of solvent aredistilled off, and then a further 100 cm³ of solvent are distilled off.After cooling to a temperature in the region of 20° C., 80 cm³ ofcyclohexane are added in the course of 10 minutes. The mixture is cooledto 0°-5° C. The slurry obtained is filtered on sintered glass and thefilter cake is washed with 40 cm³ of cyclohexane and then dried underreduced pressure at a temperature in the region of 20° C. 10.39 g of(2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine,the characteristics of which are as follows, are thereby obtained in a74% yield:

infrared spectrum (in disk with KBr): characteristic absorption bands at3100-3000, 2980, 2960, 2930, 2910, 2840, 1740, 1700, 1614, 1514, 1460,1435, 1390, 1370, 1245, 1175, 1165, 816, 760 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ;temperature: 323° K.; chemical shifts δ in ppm; coupling constants J inHz): 1.11 (s, 9H); 3.60 (s, 3H); 3.82 (s, 3H); 4.58 (d, J=5, 1H); 5.42(broad d, J=5, 1H); 6.38 (s large, 1H); 6.92 (d, J=7.5, 2H); 7.30 to7.45 (mt, 7H).

14 cm³ of an aqueous solution containing 0.31 g of lithium hydroxidemonohydrate are added to a solution of 3.0 g of the product obtainedabove in 27 cm³ of methanol. The mixture is stirred for 2 hours at atemperature in the region of 20° C. The methanol is removed bydistillation under reduced pressure and 40 cm³ of dichloromethane arethen added. With vigorous stirring, the reaction mixture is acidified byadding 1N hydrochloric acid until the pH equals 1. After settling hastaken place, the aqueous phase is separated and extracted twice with 40cm³ of dichloromethane. The combined organic phases are dried oversodium sulphate. After filtration and evaporation of the solvent, 2.88 gof(2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid, the characteristics of which are as follows, are obtained in a94.5% yield:

infrared spectrum (in disk with KBr): characteristic absorption bands at3325-2675, 2980, 2955, 2935, 2845, 1755, 1700, 1615, 1590, 1515, 1460,1250, 1175, 1030, 835, 765 and 705 cm⁻¹

proton nuclear magnetic resonance spectrum (250 MHz; CDCl₃ ; chemicalshifts a in ppm; coupling constants J in Hz): 1.08 (s, 9H); 3.82 (s,3H); 4.61 (d, J=5, 1H); 5.42 (broad d, J=5, 1H); 6.38 (broad s, 1H);6.92 (d, J=7.5 2H); 7.30 to 7.45 (mt, 7H).

EXAMPLE 2

0.52 g of dicyclohexylcarbodiimide is added at 0° C. to a stirredsolution of 1.0 g of(2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid, 1.34 g of4,acetoxy-2α-benoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxeneand 0.061 g of 4-(dimethylamino)pyridine in 7.6 cm³ of anhydroustoluene. The mixture is stirred for 2 hours at a temperature of 20° C.The dicyclohexylurea is separated by filtration and washed with toluene.The combined organic phases are washed with 0.1N hydrochloric acidsolution and saturated sodium hydrogen carbonate solution and dried oversodium sulphate. After filtration and concentration to dryness underreduced pressure, 2.09 g of crude4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateare obtained, the characteristics of which are as follows:

infrared spectrum (CHCl₃): characteristic absorption bands at 3575,1765, 1740, 1725, 1710, 1615, 1515, 1455, 1250, 1175, 980, 710 and 700cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ;temperature: 323° K.; chemical shifts δ in ppm; coupling constants J inHz): 1.09 (s, 9H); 1.18 (s, 3H); 1.27 (s, 3H); 1.67 (s, 3H); 1.72 (s,1H); 1.82 (s, 3H); 1.90 (s, 3H); 2.02 (m, 1H); 2.13 (dd, J=15 and 9,1H); 2.25 (dd, J=15 and 9, 1H); 2.60 (mt, 1H); 3.83 (d, J=7, 1H); 3.83(s, 3H); 4.12 (d, J=8, 1H); 4.26 (d, J=8, 1H); 4.60 (d, J=5, 1H); 4.61(d, J=12, 1 H); 4.78 (limiting ab, J=11, 2H); 4.90 (broad d, J=10, 1H);4.90 (d, J=12, 1H); 5.45 (broad d, J=5, 1H); 5.50 (dd, J=11 and 7, 1H);5.66 (d, J=7, 1H); 6.12 (t, J=9, 1H); 6.18 (s, 1H); 6.39 (broad s); 6.94(d, J=7.5, 2H); 7.42 (d, J=7.5, 2H); 7.35 to 7.50 (mt, 5H); 7.49 (t,J=5, 2H); 7.63 (t, J=7.5, 1H); 8.03 (d, J=7.5, 2H).

9 μl of 37% (w/w) aqueous hydrochloric acid solution are added to asolution of 0.161 g of the product obtained above in 2.1 cm³ of ethylacetate. The mixture is stirred for 3 hours at a temperature in theregion of 20° C. Assay by high performance liquid chromatography showsthat the yield of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate is 95%.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)-carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate isconverted to4-acetoxy-2α-benzoyloxy-5β,20-epoxy-9-oxo-1,7β,10β-trihydroxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (orTaxotere) under the conditions described in Patent EP 0,253,738.

EXAMPLE 3

A solution of 2.43 g of methyl(2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 0.059 gof pyridinium p-toluenesulphonate in 60 cm³ of toluene is dehydrated bydistilling off 5 cm³ of solvent. A solution of 1.7 g of3,4-dimethoxybenzaldehyde dimethyl acetal in 14 cm³ of toluene is addedin the course of 15 minutes to the reaction mixture heated to boiling.During the addition, 15 cm³ of toluene are distilled off, and then afurther 25 cm³ are distilled off. After cooling to a temperature in theregion of 20° C., 40 cm³ of water are added with stirring. Aftersettling has taken place, the organic phase is separated and dried overmagnesium sulphate. After filtration and concentration to dryness, theresidue is taken up with 8 cm³ of diisopropyl ether. The product whichcrystallizes is separated by filtration, rinsed with diisopropyl etherand then dried under reduced pressure. 1.7 g of(2R,4S,5R)-3-t-butoxycarbonylamino-2-(3,4-dimethoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine,the characteristics of which are as follows, are thereby obtained in a50% yield:

infrared spectrum (disks, mixed with KBr): characteristic absorptionbands at 3085, 3065, 3030, 2975, 2935, 2840, 1740, 1700, 1600, 1520,1495, 1455, 1425, 1265, 1175, 1025, 800, 755 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (300 MHz; DMSO-d₆ ; chemicalshifts a in ppm; coupling constants J in Hz): 1.00 (s, 9H); 3.58 (s,3H); 3.80 (s, 3H); 3.83 (s, 3H); 4.68 (d, J=4, 1H); 5.31 (unres. comp.,1H); 6.34 (unres. comp., 1H); 6.95 to 7.10 (rot., 3H); 7.35 to 7.50(mr., 5H).

0.24 g of 86% potassium hydroxide is added to a solution of 1.63 g ofthe ester thereby obtained in 25 cm³ of methanol and 7 cm³ of distilledwater. The mixture is stirred for 40 minutes at a temperature in theregion of 20° C. After removal of the methanol by distillation underreduced pressure and acidification of the medium to pH 3-4 by adding 1Nhydrochloric acid, the precipitate obtained is separated by filtration.The filter cake is washed with water and then dried. 1.45 g of(2R,4S,5R)-3-t-butoxycarbonyl-2-(3,4-dimethoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid, the purity of which is 95% and the characteristics of which are asfollows, are thereby obtained in a 92% yield:

infrared spectrum (disks, mixed with KBr): characteristic absorptionbands at 3225, 3030, 3005, 2975, 2930, 2840, 1740, 1710, 1610, 1600,1515, 1465, 1455, 1260, 1175, 1020, 760 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (250 MHz; DMSO-d₆ ; chemicalshifts δ in ppm; coupling constants J in Hz): 1.00 (s, 9H); 3.78 (s,3H); 3.81 (s, 3H); 4.55 (d, J=4, 1H); 5.23 (unres. comp. 1H); 6.29(unres. comp., 1H); 6.90 to 7.10 (mt, 3H); 7.30 to 7.50 (mt, 5H).

EXAMPLE 4

0.076 g of dicyclohexylcarbodiimide and 0.0075 g of4-(dimethylamino)pyridine are added all at once at 0° C. to a stirredsuspension of 0.155 g of(2R,4S,5R)-3-t-butoxycarbonyl-2-(3,4-dimethoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid and 0.24 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxenein 2.5 cm³ of anhydrous toluene. The mixture is stirred for 1 hour at 0°C. The dicyclohexylurea formed is separated by filtration. The cake iswashed with toluene. The combined toluene phases are washed successivelywith saturated aqueous sodium bicarbonate solution and then with water.After drying and concentration to dryness under reduced pressure, 0.435g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)-carbonyloxy-11-taxen-13α-yl(2R,4S,5R)-3-t-butoxycarbonyl-2-(3,4-dimethoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate,the characteristics of which are as follows, is obtained in aquantitative yield:

infrared spectrum (CCl₄): characteristic absorption bands at 3580,3550-3375, 3090, 3070, 3030, 1765, 1740, 1730, 1715, 1605, 1520, 1500,1465, 1455, 1265, 1250, 1180, 1035, 985, 710 and 695 cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ;temperature: 323° K.; chemical shifts δ in ppm; coupling constants J inHz): 1.10 (s, 9H); 1.17 (s, 3H); 1.25 (s, 3H); 1.66 (s, 3H); 1.70 (s,1H); 1.82 (s, 3H); 1.90 (s, 3H); 2.02 (mt, 1H); 2.13 (dd, J=15 and 9,1H); 2.24 (dd, J=15 and 9, 1H); 2.60 (mt, 1H); 3.83 (d, J=7, 1H); 3.89(s, 3H); 3.93 (s, 3H); 4.12 (d, J=8, 1H); 4.26 (d, J=8, 1H); 4.60 (d,J=4.5, 1H); 4.60 (d, J=12, 1H); 4.78 (limiting ab, 2H); 4.89 (broad d,J=10, 1H); 4.90 (d, J=12, 1H); 5.46 (broad d, J=4.5, 1H); 5.50 (dd, J=11and 7, 1H); 5.66 (d, J=7, 1H); 6.13 (t, J=9, 1H); 6.15 (s, 1H); 6.39 (s,1H); 6.90 (d, J=7.5, 1H); 7.03 (d, J=1, 1H); 7.07 (dd, J=7.5 and 1, 1H);7.35 to 7.50 (mt, 5H); 7.48 (t, J=7.5, 2H); 7.62 (t, J=7.5, 1H); 8.03(d, J=7.5, 2H) .

2 μl of methanesulphonic acid are added to a solution of 0.223 g of theester obtained above in 2.5 cm³ of methanol. The mixture is stirred for2 hours 30 minutes at a temperature in the region of 20° C. Assay byhigh performance liquid chromatography shows that the yield of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxy-carbonylamino-3-phenyl-2-hydroxypropionate is 88%.

EXAMPLE 5

A solution of 0.497 g of methyl(2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.012 g ofpyridinum b-toluenesulphonate and 0.295 g of 2,4-dimethoxybenzaldehydein 20 cm³ of anhydrous toluene is heated to reflux for 24 hours. Thewater formed during the reaction is removed by means of a Dean and Starkapparatus. After cooling to a temperature in the region of 20° C., thesolution is washed with 37% (w/w) aqueous sodium hydrogen sulphitesolution and then with saturated aqueous sodium bicarbonate solution.After concentration of the organic phase under reduced pressure, 0.700 gof(4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidineis obtained in an 80% yield in the form of a virtually equimolecularmixture of the diastereo-isomeric forms A and B, the characteristics ofwhich are as follows:

infrared spectrum (CCl₄): characteristic absorption bands at 3095, 3070,3035, 2980, 2955, 2935, 2840, 1760, 1745, 1710, 1615, 1590, 1510, 1465,1455, 1435, 1210, 1160, 1040, 835 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (250 MHz; DMSO-d₆ ; chemicalshifts δ in ppm; coupling constants J in Hz): 1.00 (s, --C(CH₃)₃ of B) ;1.22 (s, --C(CH₃)₃ of A); 3.55 (unres. comp. --COOCH₃ or --OCH₃ of B);3.87 to 3.85 (mt, --COOCH₃ or --OCH₃ of A and B); 4.64 (d, J=4.5, --H5of B); 5.01 (d, J=2.5, --H5 of A); 5.21 (d, J=2.5, --H4 of A); 5.26 (d,J=4.5, --H4 of B); 6.46 [dd, J=7.5 and 1.5, --C₆ H₅ at position 2 (--H5)of A]; 6.52 (s, --H2 of A); 6.50-6.65 [mt, --H2 and --C₆ H₅ at position2 (--H5 and --H3) of B+--C₆ H₅ at position 2 (--H3) of A]; 7.00 [d,J=7.5, --C₆ H₅ at position 2 (--H6) of B]; 7.30 to 7.55 (mt, 5H, --C₆ H₅at position 4 (--H2 to --H6) of A and B].

0.073 g of lithium hydroxide monohydrate is added to a solution of 0.700g of the ester obtained above in a mixture of 9 cm³ of methanol and 3cm³ of distilled water. The resulting mixture is stirred for 3 hours 30minutes at a temperature in the region of 20° C. The methanol is removedby distillation under reduced pressure. The aqueous phase is washed withtoluene and is then acidified until the pH equals 3-4 by adding 1Naqueous hydrochloric acid solution. The precipitate obtained isseparated by filtration, and the filter cake is washed copiously withwater to neutrality and then dried under reduced pressure. 0.450 g of(4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethylphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid is thereby obtained in a 74% yield in the form of a virtuallyequimolecular mixture of the diastereoisomeric forms A and B, thecharacteristics of which are as follows:

infrared spectrum (in disk with KBr): characteristic absorption bands at3300-2700, 2700-2250, 3070, 3030, 3005, 2975, 2940, 2840, 1710, 1615,1590, 1510, 1460, 1210, 1160, 1035, 835 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (200 MHz; DMSO-d₆ ;temperature: 393° K.; chemical shifts δ in ppm; coupling constants J inHz; mixture of the 2 diastereoisomers in the proportion 55:45): 1.00 (s,--C(CH₃)₃ of B); 1.25 (s, --C(CH₃)₃ of A); 3.75 to 3.85 (mt, 6H, --OCH₃of A and B); 4.43 (d, J=5, --H5 of B); 4.77 (d, J=2, --H5 of A); 5.21(d, J=2, --H4 of A); 5.21 (d, J=2, --H4 of B); 6.42 [dd, J=7.5 and 1.5,--C₆ H₅ at position 2 (--H5) of A]; 6.49 (s, --H2 of A); 6.45-6.60 [mt,H2 and --C₆ H₅ at position 2 (--H5 and --H3) of B+--C₆ H₅ at position 2(--H3) of A]; 7.02 [d, J=7.5, --C₆ H₅ at position 2 (--H6) of A]; 7.15[d, J=7.5, --C₆ H₅ at position 2 (--H6) of B]; 7.25 to 7.50 [rot, 5H,--C₆ H₅ at position 4 (--H2 to --H6) of A and B].

EXAMPLE 6

0.656 g of dicyclohexylcarbodiimide and 0.0287 g of4-(dimethylamino)pyridine are added all at once at 0° C. to a stirredsuspension of 1.671 g of(4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid and 1.003 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxene in 8 cm³ of anhydrous toluene. The mixture isstirred for 10 minutes at 0° C. and then for 5 hours at a temperature inthe region of 20° C. The dicyclohexylurea formed is separated byfiltration and washed with toluene. The combined toluene phases arewashed with saturated aqueous sodium bicarbonate solution and then withwater. After drying, filtration and concentration to dryness underreduced pressure, 1.623 g of crude4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethoxyphenyl)-4-1,3-oxazolidine-5-carboxylateare obtained in the form of a diasteroisomeric mixture, the constituentsof which are separated by liquid chromatography on silica gel, elutingwith an ethyl acetate/cyclohexane mixture (75:25 by volume).

One of the two diastereoisomers possesses the following characteristics:

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ; chemicalshifts a in ppm; coupling constants J in Hz): 1.20 (s, 3H); 1.25 (s,9H); 1.30 (s, 3H); 1.76 (s, 1H); 1.85 (s, 3H); 2.00 (s, 3H); 2.05 (mt,1H); 2.17 (s, 3H); 2.26 (dd, J=15 and 9, 1H); 2.34 (dd, J =15 and 9,1H); 2.60 (mt, 1H); 3.82 (s, 3H); 3.92 (s, 3H); 3.95 (d, J=7, 1H); 4.14(d, J=8, 1H); 4.30 (d, J=8, 1H); 4.62 (d, J=12, 1H); 4.80 (limiting ab,2H); 4.90 (mt, 1H); 4.92 (mt, 1H); 4.92 (d, J=12, 1H); 5.36 (d, J=2,1H); 5.63 (dd, J=11 and 7, 1H); 5.70 (d, J=7, 1H); 6.28 (s, 1H); 6.34(t, J=9, 1H); 6.43 (dd, J=7.5 and 1.5, 1H); 6.51 (d, J=1.5, 1H); 6.69(s, 1H); 7.16 (d, J=7.5, 1H); 7.35 to 7.50 (mt, 3H); 7.48 (t, J=7.5,2H); 7.67 (d, J=7.5, 2H); 7.63 (t, J=7.5, 1H); 8.04 (d, J=7.5, 2H).

The other diasteroisomer possesses the following characteristics:

infrared spectrum (CCl₄): characteristic absorption bands at 3580,3550-3300, 3070, 3030, 1760, 1740, 1710, 1610, 1590, 1510, 1455, 1435,1260, 1250, 1210, 1180, 1035, 985, 710 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ; chemicalshifts δ in ppm; coupling constants J in Hz): 1.10 [s, 9H: --C(CH₃)₃ ];11.16 (s, 3H: --CH₃ 16 or 17); 1.24 (s, 3H: --CH₃ 16 or 17); 1.53 (s,3H: --CH₃ 19); 1.66 (s, 1H: --OH 1); 1.82 (s, 3H: --CH₃ 18); 2.00 (s,3H: --COCH₃); 2.00 (mt, 1H: --(CH)--H6); 2.12 (dd, J=15 and 9, 1H:--(CH)--H14); 2.24 (dd, J=15 and 9, 1H: --(CH)--H14); 2.60 (mt, 1H:--(CH)--H6); 3.82 (d, J=7, 1H: --H3); 3.82 (s, 3H: --OCH₃); 3.90 (s, 3H:--OCH₃); 4.12 (d, J=8, 1H: --(CH)--H20); 4.26 (d, J=8, 1H: --(CH)--H20);4.55 (d, J=4, 1H: H5'); 4.62 (d, J=12, 1H: --O(CH)--H of CCl₃ CH₂ OCOOat position 7); 4.78 (ab, J=11, 2H: O--CH₂ of Cl₃ CH₂ OCOO at position-10); 4.89 (broad d, J=10, 1H: --H5); 4.89 (d; J=12, 1H: --O(CH)--H ofCl₃ CCH₂ OCOO at position -7); 5.46 (broad d, J=4, 1H: H4'); 5.50 (dd,J=11 and 7, 1H: --H7); 5.65 (d, J=7, 1H: --H2); 6.05 (t, J=9, 1H:--H13); 6.16 (s, 1H: --H10); 6.50 [mt, 2H: --C₆ H₅ at position 2' (--H3and H5) ]; 6.72 (unres. comp., 1H: H2'); 7.22 [d, J=7.5, 1H: --C₆ H₅ atposition 2' (--H6)]; 7.30 to 7.50 [mt, 5H: --C₆ H₅ at position 4' (--H2to --H6)]; 7.48 [t, J=7.5, 2H: --OCOC₆ H₅ (--H3 and --H5)]; 7.63 [t,J=7.5, 1H: --OCOC₆ H₅ (--H4)]; 8.03 [d, J=7.5, 2H: --OCOC₆ H₅ (--H2 and--H6)].

80 μl of methanesulphonic acid are added to a solution of 1.623 g of thecrude ester obtained above in 20 cm³ of methanol. The mixture is stirredfor 4 hours at a temperature in the region of 20° C. Assay by highperformance liquid chromatography shows that the yield of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate is 88%.

EXAMPLE 7

A solution of 10.0 g of methyl(2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 1.0 g ofpyridinium p-toluenesulphonate and 5.7 cm³ of benzaldehyde dimethylacetal in 250 cm³ of anhydrous toluene is heated to reflux. 200 cm³ ofsolvent are distilled off in the course of 2 hours. The solution iscooled to a temperature in the region of 20° C. and washed with 50 cm³of water. After settling has taken place, and separation, drying andconcentration to dryness of the organic phase, the residue obtained istaken up in 14 cm³ of diisopropyl ether. The slurry obtained isfiltered, rinsed and drained. 8.4 g of(2R,4S,5R)-S-t-butoxycarbonylamino-2,4-diphenyl-5-methoxycarbonyl-1,3-oxazolidineare thereby obtained in a 65% yield in the form of a singlediastereoisomer, the characteristics of which are as follows:

infrared spectrum (disk, mixed with KBr): characteristic absorptionbands at 3250, 3095, 3070, 3030, 2975, 1710, 1500, 1460, 1165, 760 and700 cm⁻¹

proton nuclear magnetic resonance spectrum (300 MHz; DMSO-d₆ ; chemicalshifts δ in ppm; coupling constants J in Hz): 0.95 (s, 9H); 4.26 (unres.comp., 1H); 5.10 (unres. comp. 1H); 6.20 (s, 1H); 7.25-7.55 (mr, 5H).

1.26 g of 86% potassium hydroxide are added to a solution of 7.07 g ofthe ester obtained above in 88 cm³ of methanol and 22 cm³ of water. Themixture is stirred overnight at a temperature in the region of 25° C.The methanol is removed by distillation under reduced pressure. Themixture is acidified by adding 1N hydrochloric acid until the pH equals2. The precipitate obtained is separated by filtration, washed copiouslywith water to neutrality and then dried under reduced pressure. 7.0 g of(2R,4S,5R)-3-t-butoxycarbonyl-2,4-diphenyl-1,3-oxazolidine-5-carboxylicacid are thereby obtained in a quantitative yield in the form of asingle diastereoisomer, the characteristics of which are as follows:

infrared spectrum (disk, mixed with KBr): main characteristic absorptionbands at 3080, 3050, 3030, 3005, 2975, 1760, 1695, 1600, 1585, 1490,1460, 1435, 1175, 760 and 700 cm⁻¹

proton nuclear magnetic resonance spectrum (200 MHz; DMSO-d₆ ; chemicalshifts a in ppm; coupling constants J in Hz): 0.98 (s, 9H); 3.38 (s,3H); 4.71 (d, J=4, 1H); 5.30 (broad d, J=4, 1H); 6.38 (s, 1H); 7.25 to7.55 (mt, 5H).

EXAMPLE 8

0.70 g of dicyclohexylcarbodiimide and 0.030 g of4-(dimethylamino)pyridine are added to a stirred suspension of 1.25 g of(2R,4S,5R)-3-t-butoxycarbonyl-2,4-diphenyl-1,3-oxazolidine-5-carboxylicacid and 1.08 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)-carbonyloxy-11-taxenein 12 cm³ of anhydrous toluene. The mixture is stirred for 24 hours at atemperature in the region of 20° C. The dicyclohexylurea formed isseparated by filtration and washed with toluene. The combined organicphases are washed with saturated aqueous sodium bicarbonate solution.After drying and concentration to dryness under reduced pressure, 2.27 gof a crude product are obtained, which product is purified by liquidchromatography on silica gel, eluting with a hexane/ethyl acetatemixture (1:1 by volume). 1.05 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)-carbonyloxy-11-taxen-13α-yl(2R,4S,5R)-3-t-butoxycarbonyl-2,4-diphenyl-1,3-oxazolidine-5-carboxylateare thereby obtained in a 75% yield in the form of a singlediastereoisomer, the characteristics of which are as follows:

infrared spectrum (in disk with KBr): main characteristic absorptionbands at 3250, 3095, 3070, 3030, 2975, 1710, 1500, 1460, 1165, 760 and700 cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ; chemicalshifts δ in ppm; coupling constants J in Hz): 1.05 (s, 9H); 1.15 (s,3H); 1.25 (s, 3H); 1.63 (s, 3H); 1.73 (s, 1H); 1.80 (s, 3H); 1.87(unres. comp. 3H); 2.01 (mt, 1H); 2.08 (dd, J=15 and 9, 1H); 2.23 (dd,J=15 and 9, 1H); 2.58 (mt, 1H); 3.81 (d, J=7, 1H); 4.10 (d, J=8, 1H);4.26 (d, J=8, 1H); 4.60 (d, J=12, 1H); 4.61 (d, J=4, 1H); 4.78 (ab,J=11, 2H); 4.87 (broad d, J=10, 1H); 4.90 (d, J=12, 1H); 5.46 (mr, 1H);5.50 (dd, J=11 and 7, 1H); 5.63 (d, J =7, 1H); 6.13 (mt, 1H); 6.13 (s,1H); 6.43 (unres. comp., 1H); 7.35 to 7.50 (mr, 10H); 7.48 (t, J=7.5,2H); 7.62 (t, J=7.5, 1H); 8.03 (d, J=7.5, 2H).

2.6 μl of methanesulphonic acid are added to a solution of 41 mg of theester obtained above in 0.4 cm³ of methanol. The mixture is stirred for48 hours at a temperature in the region of 20° C. Assay by highperformance liquid chromatography shows that4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxy-propionate isobtained in a 50% yield.

EXAMPLE 9

A solution of 10.0 g of methyl(2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.334 g ofpyridinium p-toluenesulphonate and 3.75 cm³ of trimethyl orthoformate in70 cm³ of toluene is heated to reflux. 4 cm³ of solvent are distilledoff. After cooling to a temperature in the region of 20° C. andfiltration, the filtrate is concentrated to dryness under reducedpressure. The residue is taken up with 50 cm³ of hexane. The slurryobtained is filtered, rinsed and drained. 4.6 g of(4S,5R)-3-t-butoxycarbonyl-2-methoxy-4-phenyl-5-methoxycarbonyl-1,3-oxazolidineare thereby obtained in a 40% yield in the form of a mixture ofdiastereoisomers, the characteristics of which are as follows:

infrared spectrum (CH₂ Cl₂): characteristic absorption bands at 2980,2955, 2935, 2840, 1760, 1745, 1710, 1495, 1460, 1440, 1175, 1080 and1065 cm⁻¹

proton nuclear magnetic resonance spectrum (300 MHz; DMSO-d₆ ;temperature: 393° K.; chemical shifts δ in ppm; coupling constants J inHz) on the 65:35 mixture of diastereoisomers: 1.22 (s, 3H); 1.32 (s,3H); 3.34 (s, 3H); 3.43 (s, 3H); 3.75 (s, 3H); 4.55 (d, J=3, 1H); 4.68(d, J=8, 1H); 4.98 (d, J=8, 1H); 5.17 (d, J=3, 1H); 6.10 (s, 1H); 6.13(s, 1H); 7.20 to 7.50 (mt, 5H).

16.1 g of lithium hydroxide monohydrate are added to a solution of 11.27g of the product obtained above in 85 cm³ of methanol and 28 cm³ ofwater. The mixture is stirred for 30 minutes at a temperature in theregion of 20° C. The methanol is removed by distillation under reducedpressure, and 145 cm³ of water and 245 cm³ of ethyl acetate are thenadded. The two-phase mixture is cooled to 0° C. with stirring and thenacidified with 1N hydrochloric acid until the pH equals 5. The aqueousphase is separated after settling has taken place and extracted withtwice 75 cm³ of ethyl acetate. The organic phases are combined and driedover sodium sulphate. After filtration and concentration under reducedpressure at 25° C. to a volume of 50 cm³, 9.80 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxy)-carbonyloxy-11-taxene,4.29 g of dicyclohexyl-carbodiimide and 0.25 g of4-(dimethylamino)pyridine are added to this residual solution at 0° C.The mixture is stirred for 15 minutes at 0° C. for 3 hours at atemperature in the region of 20° C. The dicyclohexylurea formed isseparated by filtration and washed with ethyl acetate. The combinedorganic phases are washed with saturated aqueous sodium bicarbonatesolution. After drying and concentration to dryness under reducedpressure, 14.75 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(4S,5R)-3-t-butoxycarbonyl-2-methoxy-4-phenyl-1,3-oxazolidine-5-carboxylateare obtained in the form of a diastereoisomeric mixture, thecharacteristics of which are as follows:

infrared spectrum (CH₂ Cl₂): characteristic absorption bands at 1760,1725-1710, 1600, 1450, 1245, 1175, 1060, 985 and 815 cm⁻¹

proton nuclear magnetic resonance spectrum (400 MHz; CDCl₃ ;temperature: 323° K.; chemical displacements δ in ppm; couplingconstants J in Hz): 1.23 (s, 3H); 1.32 (s, 3H); 1.35 (unres. comp., 9H);1.88 (s, 3H); 1.91 (s, 3H); 2.08 (s, 3H); 2.08 (mt, 1H); 2.26 (split ab,J=15 and 9, 1H); 2.65 (mt, H); 3.65 (s, 3H); 3.92 (d, J=7, 1H); 4.18 (d,J=8, 1H); 4.31 (d, J=8, 1H); 4.64 (d, J=12, 1H); 4.80 (d, J=7, 1H); 4.83(limiting ab, 2H); 4.95 (broad d, J=10, 1H); 4.95 (d, J=12, 1H); 5.04(broad d, J=7, 1H); 5.58 (dd, J=11 and 7, 1H); 5.72 (d, J=7, 1H); 6.25(s, 1H); 6.31 (s, 1H); 6.34 (t, J=9, 1H); 7.30 to 7.55 (mt, 5H); 7.54(t, J=7.5, 2H); 7.68 (t, J=7.5, 1H); 8.08 (d, J=7.5, 2H).

47 μl of 37% (w/w) hydrochloric acid are added to a stirred solution of0.617 g of ester obtained above in 7.6 cm³ of ethyl acetate. The mixtureis stirred for 20 hours at a temperature in the region of 20° C.Analysis by high performance liquid chromatography shows that4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7.beta.,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate is obtainedin a 53% yield.

EXAMPLE 10

A solution of 4.01 g of methyl(2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate and 0.01 g ofpyridinium p-toluenesulphonate in 70 cm³ of toluene is dehydrated bydistilling off 30 cm³ of solvent. 30 cm³ of toluene are added and 20 cm³of solvent are distilled off. After cooling, a solution of 2.57 g ofp-methoxybenzaldehyde dimethyl acetal in 6 cm³ of toluene is added. 20cm³ of toluene are added, and the mixture is then heated for 40 minutesto a temperature in the region of 100° C. while distilling off 60 cm³ ofsolvent. After cooling, the cloudy solution is filtered through cottonwool and then concentrated to dryness. 6.13 g of a yellowish oil arethereby obtained, which oil is stirred for 12 hours with 30 cm³ ofcyclohexane. After filtration on sintered glass and washing of theprecipitate with twice 10 cm³ of cyclohexane, 5.09 g of (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidineare obtained in a 91% yield.

25 cm³ of an aqueous solution containing 834 mg of 86% potassiumhydroxide are added to a solution of 4.80 g of the product obtainedabove in 120 cm³ of methanol. The mixture is stirred for 1 hour at atemperature in the region of 20° C. The methanol is removed bydistillation under reduced pressure, and 25 cm³ of water and 50 cm³ ofisopropyl ether are then added. The aqueous phase is separated aftersettling has taken place and then washed with twice 25 cm³ of isopropylether. The aqueous phase is acidified by adding concentratedhydrochloric acid until the pH equals 1, and 50 cm³ of dichloromethaneare then added. After settling has taken place, the aqueous phase isseparated and washed with 25 cm³ of dichloromethane. The combinedorganic phases are washed with 25 cm³ of water and then dried oversodium sulphate. After filtration and concentration to dryness, 4.49 gof(2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylicacid are obtained in a 97% yield.

EXAMPLE 11

A solution of 0.1023 g of(2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3oxazolidine-5-carboxylicacid and 5.2 mg of 4-(dimethylamino)pyridine in 3 cm³ of toluene isadded to a solution of 0.137 g of 85%4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β-triethylsilyloxy-11-taxeneand 0.0521 g of dicyclohexylcarbodiimide in 1 cm³ of toluene. Themixture is stirred for 2 hours 15 minutes at a temperature in the regionof 20° C. The dicyclohexylurea is separated by filtration. 20 cm³ ofsaturated sodium bicarbonate solution are added to the filtrate. Aftersettling has taken place, the aqueous phase is separated and extractedwith 3 times 30 cm³ of dichloromethane. The combined organic phases aredried over sodium sulphate. After filtration and concentration, 0.2108 gof a product is obtained, which product is purified by chromatography on7 g of silica contained in a column 30 cm in height and 1.5 cm indiameter, eluting with a cyclohexane/ethyl acetate mixture (70:30 byvolume). 127.4 mg of4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β-triethylsilyloxy-11-taxen-13α-yl(2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate,the structure of which is confirmed by the proton nuclear magneticresonance spectrum and the purity of which is in the region of 95%, arethereby obtained in a 70.54% yield.

400 μl of a 0.9N ethanolic solution of hydrochloric acid are added to asolution of 40 mg of the product obtained above in 2 cm³ of ethanol. Themixture is stirred for 6 hours at a temperature in the region of 20° C.Assay by high performance liquid chromatography shows that the yield of4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β-dihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-benzoyl-3-phenylpropionate (or taxol) is 51.4%.

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. A process for preparing a product of formula (IX):##STR16## in which G'₁ represents a hydrogen atom or a group protectingthe hydroxyl function,G'₂ represents a hydrogen atom, an acetyl radical,or a group protecting the hydroxyl function, R₁ represents a benzoylradical or a radical R₂ --O--CO-- in which R₂ represents: an unbranchedor branched alkyl radical containing 1 to 8 carbon atoms, an alkenylradical containing 2 to 8 carbon atoms, an alkynyl radical containing 3to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, wherein these radicals definedfor R₂ are optionally substituted with at least one substituent selectedfrom halogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to4 carbon atoms, dialkylamino radicals in which each alkyl portioncontains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals, said 1-piperazinyl radicals being optionallysubstituted at position 4 with an alkyl radical containing 1 to 4 carbonatoms or with a phenylalkyl radical in which the alkyl portion contains1 to 4 carbon atoms, cycloalkyl radicals containing 3 to 6 carbon atoms,cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals,cyano radicals, carboxyl radicals, and alkyloxycarbonyl radicals inwhich the alkyl portion contains 1 to 4 carbon atoms, wherein saidcycloalkyl, cycloalkenyl and bicycloalkyl radicals can be optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, or a phenyl radical optionally substituted with at least onesubstituent selected from halogen atoms and radicals selected from alkylradicals containing 1 to 4 carbon atoms and alkyloxy radicals containing1 to 4 carbon atoms, or a saturated or unsaturated nitrogenousheterocyclic radical containing 5 or 6 ring atoms and being optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, andAr represents a phenyl or α- or β-naphthyl radical optionallysubstituted with at least one substituent selected from fluorine,chlorine, bromine, and iodine atoms and alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl,mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano and trifluoromethyl radicals, wherein the alkylradicals and alkyl portions of said above radicals independently contain1 to 4 carbon atoms, and the alkenyl and alkynyl radicals independentlycontain 3 to 8 carbon atoms and the aryl radicals and aryl portions ofsaid above radicals are independently selected from phenyl and α- andβ-naphthyl radicals, said process comprising the steps of: (A)esterifying a protected 10-deacetylbaccatin III or baccatin IIIderivative of formula (III): ##STR17## in which G₁ represents a groupprotecting the hydroxyl function and G₂ represents an acetyl radical ora group protecting the hydroxyl function, by means of an acid or salt offormula (VII): ##STR18## in which Ar and R₁ are defined as above and R₃represents a hydrogen atom, an alkoxy radical containing 1 to 4 carbonatoms, or an optionally substituted aryl radical,or by means of aderivative of said acid of formula (VII), to obtain a product of formula(VIII): ##STR19## in which Ar, R₁, R₃, G₁ and G₂ are defined as above,(B) deprotecting the side chain of said product of formula (VIII) and(C) optionally deprotecting at least one of the G₁ and G₂ -protectedhydroxyl functions of said product of formula (VIII), to obtain saidproduct of formula (IX).
 2. Process according to claim 1, wherein theesterification is performed by means of an acid of formula VII or one ofits derivatives for which, Ar and R₁ are defined as in claim 1, R₃represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbonatoms or a phenyl radical optionally substituted with electron-donatingradical.
 3. Process according to claim 2, wherein the electron-donatingradicals are selected from alkoxy radicals containing 1 to 4 carbonatoms.
 4. Process according to claim 1, wherein the groups protectingbaccatin III or 10-deacetylbaccatin III represented by G₁ and G₂ areselected from (2,2,2-trichloroethoxy)carbonyl and2-(2-trichloromethylpropoxy)carbonyl radicals and trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which thealkyl portions contain 1 to 4 carbon atoms and the aryl portions arephenyl radicals.
 5. Process according to claim 1, wherein theesterification by means of an acid of formula (VII): ##STR20## in whichAr and R₁ are defined as in claim 1 and R₃ is defined as in claim 1, isperformed in the presence of a condensing agent and an activating agent,working in an organic solvent at a temperature of from -10° to 90° C. 6.Process according to claim 5, wherein the condensing agent is selectedfrom carbodiimides and reactive carbonates and the activating agent isselected from aminopyridines.
 7. Process according to claim 6, whereinthe condensing agent is selected from dicyclohexylcarbodiimide anddi-2-pyridyl carbonate and the activating agent is selected from4-(dimethylamino)-pyridine and 4-pyrrolidinopyridine.
 8. Processaccording to claim 5, wherein the solvent is selected from ethers,ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons.
 9. Process according to claim 8,wherein the solvent is selected from aromatic hydrocarbons.
 10. Processaccording to claim 1 wherein, said derivative of said acid of formula(VII) is an anhydride of formula (X): ##STR21## in which Ar and R₁ aredefined as in claim 1 and R₃ is defined in claim 1, wherein said step ofesterification is carried out in the presence of an activating agent inan organic solvent at a temperature ranging from 0° to 90° C. 11.Process according to claim 10, wherein the activating agent is selectedfrom aminopyridines.
 12. Process according to claim 11, wherein theactivating agent is selected from 4-(dimethylamino)pyridine and4-pyrrolidinopyridine.
 13. Process according to claim 10, wherein thesolvent is selected from ethers, ketones, esters, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons and aromatichydrocarbons.
 14. Process according to claim 1 wherein, said derivativeof said acid of formula (VII) is an activated acid of formula (XI):##STR22## in which Ar and R₁ are defined as in claim 1 and R₃ is definedin claim 1 and X represents a halogen atom or an acyloxy or aryloxyradical, optionally prepared in situ, wherein said step ofesterification is carried out in the presence of a base in an organicsolvent at a temperature ranging from 10° to 80° C.
 15. Processaccording to claim 14, wherein the base is selected from nitrogenousorganic bases.
 16. Process according to claim 15, wherein thenitrogenous organic base is selected from aliphatic tertiary amines,pyridine and aminopyridines.
 17. Process according to claim 14, whereinthe solvent is selected from ethers, ketones, esters, nitriles,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatichydrocarbons.
 18. Process according to claim 17, wherein the solvent isselected from aromatic hydrocarbons.
 19. Process according to claim 1wherein, said protecting groups G₁ and G₂ are silyl protective groupsand wherein the deprotection of the side chain and, optionally, of thehydroxyl functions protected by said silyl protective groups G₁ and G₂is performed in the presence of an inorganic or organic acid or mixturesthereof, working in an organic solvent at a temperature ranging from-10° to 60° C.
 20. Process according to claim 19, wherein the inorganicacid is selected from hydrochloric and sulphuric acids and the organicacid is selected from acetic, methanesulphonic,trifluoromethanesulphonic and p-toluenesulphonic acids.
 21. Processaccording to claim 19, wherein the solvent is selected from alcohols,ethers, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons.
 22. Process according to claim1, wherein the deprotection of the side chain is performed in thepresence of an oxidizing agent in water or in an aqueous-organic medium.23. Process according to claim 22, wherein the oxidizing agent isammonium cerium IV nitrate in an aqueous-organic medium.
 24. Processaccording to claim 22, wherein the aqueous-organic medium is awater/acetonitrile mixture.
 25. Process according claim 22, wherein theoxidizing agent is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in water.26. Process according to claim 1, wherein the deprotection of the sidechain is performed by hydrogenolysis.
 27. Process according to claim 26,wherein the hydrogenolysis is performed with hydrogen in the presence ofa catalyst.
 28. Process according to claim 1, wherein replacement by ahydrogen atom of the protective group G₁ and optionally, the group G₂,wherein G₂ represents a 2,2,2-trichloroethoxycarbonyl or2-(2-trichloromethyl-propoxy) carbonyl radical is performed with zinc,optionally in the presence of acetic acid at a temperature from 20° to60° C., or by means of an acid dissolved in an aliphatic alcoholcontaining 1 to 3 carbon atoms or in an aliphatic ester, in the presenceof zinc optionally in combination with copper.
 29. An acid of formula(VII): ##STR23## in which Ar and R₁ are defined as in claim 1 and R₃ isdefined in claim 1, optionally in the form of a salt, ester, anhydride,mixed anhydride or halide.
 30. A product of general formula (VII):##STR24## in which Ar and R₁ are defined as in claim 1, R₃ is defined inclaim 1 and G₁ and G₂ are defined in claim
 1. 31. A process according toclaim 1, wherein in said formula (lII), G₂ represents an acetyl radical,and further wherein in said formula (IX), G'₂ represents an acetylradical.
 32. A process according to claim 1, wherein said derivative ofsaid acid of formula (VII) is an ester, an anhydride, a mixed anhydrideor a halide.
 33. A process according to claim 1, wherein in saidoptional step (C), the G₁ -protected hydroxyl function of said productof formula (VIII) is deprotected to obtain a taxane derivative offormula (I).
 34. A process for preparing a product of formula (VIII):##STR25## in which G₁ represents a group protecting the hydroxylfunctionG₂ represents an acetyl radical or a group protecting thehydroxyl function, Ar represents a phenyl or α- or β-naphthyl radicaloptionally substituted with at least one substituent selected fromfluorine, chlorine, bromine, and iodine atoms and alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio,hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano and trifluoromethylradicals, wherein the alkyl radicals and alkyl portions of said aboveradicals independently contain 1 to 4 carbon atoms, and the alkenyl andalkynyl radicals independently contain 3 to 8 carbon atoms and the arylradicals and aryl portions of said above radicals are independentlyselected from phenyl and α- and β-naphthyl radicals, R₁ represents abenzoyl radical or a radical R₂ --O--CO-- in which R₂ represents: anunbranched or branched alkyl radical containing 1 to 8 carbon atoms, analkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 10 carbon atoms, wherein theseradicals defined for R₂ are optionally substituted with at least onesubstituent selected from halogen atoms, hydroxyl radicals, alkyloxyradicals containing 1 to 4 carbon atoms, dialkylamino radicals in whicheach alkyl portion contains 1 to 4 carbon atoms, piperidino radicals,morpholino radicals, 1-piperazinyl radicals, said 1-piperazinyl radicalsbeing optionally substituted at position 4 with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains 1 to 4 carbon atoms,cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl radicals, cyano radicals, carboxyl radicals, andalkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4carbon atoms, wherein said cycloalkyl, cycloalkenyl and bicycloalkylradicals can be optionally substituted with at least one alkyl radicalcontaining 1 to 4 carbon atoms, or a phenyl radical optionallysubstituted with at least one substituent selected from halogen atomsand radicals selected from alkyl radicals containing 1 to 4 carbon atomsand alkyloxy radicals containing 1 to 4 carbon atoms, or a saturated orunsaturated nitrogenous heterocyclic radical containing 5 or 6 ringatoms and being optionally substituted with at least one alkyl radicalcontaining 1 to 4 carbon atoms, and R₃ represents a hydrogen atom, analkoxy radical containing 1 to 4 carbon atoms, or an optionallysubstituted aryl radical, said process comprising the step of:esterifying a protected 10-deacetylbaccatin III or baccatin IIIderivative of formula (III): ##STR26## in which G₁ and G₂ are as definedabove by means of an acid or salt of formula (VII): ##STR27## in whichAr, R₁ and R₃ are defined as above, or by means of a derivative of saidacid of formula (VII), to obtain said product of formula (VIII).
 35. Aprocess for preparing a product of formula (IX): ##STR28## in which G'₁represents a hydrogen atom or a group protecting the hydroxylfunction,G'₂ represents a hydrogen atom, an acetyl radical, or a groupprotecting the hydroxyl function, R₁ represents a benzoyl radical or aradical R₂ --O--CO-- in which R₂ represents: an unbranched or branchedalkyl radical containing 1 to 8 carbon atoms, an alkenyl radicalcontaining 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, acycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, wherein these radicals definedfor R₂ are optionally substituted with at least one substituent selectedfrom halogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to4 carbon atoms, dialkylamino radicals in which each alkyl portioncontains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals, said 1-piperazinyl radicals being optionallysubstituted at position 4 with an alkyl radical containing 1 to 4 carbonatoms or with a phenylalkyl radical in which the alkyl portion contains1 to 4 carbon atoms,cycloalkyl radicals containing 3 to 6 carbon atoms,cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals,cyano radicals, carboxyl radicals, and alkyloxycarbonyl radicals inwhich the alkyl portion contains 1 to 4 carbon atoms, wherein saidcycloalkyl, cycloalkenyl and bicycloalkyl radicals can be optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, or a phenyl radical optionally substituted with at least onesubstituent selected from halogen atoms and radicals selected from alkylradicals containing 1 to 4 carbon atoms and alkyloxy radicals containing1 to 4 carbon atoms, or a saturated or unsaturated nitrogenousheterocyclic radical containing 5 or 6 ring atoms and being optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, andAr represents a phenyl or α- or β-naphthyl radical optionallysubstituted with at least one substituent selected from fluorine,chlorine, bromine, and iodine atoms and alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl,mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano and trifluoromethyl radicals, wherein the alkylradicals and alkyl portions of said above radicals independently contain1 to 4 carbon atoms, and the alkenyl and alkynyl radicals independentlycontain 3 to 8 carbon atoms and the aryl radicals and aryl portions ofsaid above radicals are independently selected from phenyl and α- andβ-naphthyl radicals, said process comprising the steps of: (A)deprotecting the side chain of a product of formula (VIII): ##STR29## inwhich Ar represents a phenyl or α- or β-naphthyl radical optionallysubstituted with at least one substituent selected from fluorine,chlorine, bromine, and iodine atoms and alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl,mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano and trifluoromethyl radicals, wherein the alkylradicals and alkyl portions of said above radicals independently contain1 to 4 carbon atoms, and the alkenyl and alkynyl radicals independentlycontain 3 to 8 carbon atoms and the aryl radicals and aryl portions ofsaid above radicals are independently selected from phenyl and α- andβ-naphthyl radicals, R₁ represents a benzoyl radical or a radical R₂--O--CO-- in which R₂ represents: an unbranched or branched alkylradical containing 1 to 8 carbon atoms, an alkenyl radical containing 2to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, acycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenylradical containing 4 to 6 carbon atoms or a bicycloalkyl radicalcontaining 7 to 10 carbon atoms, wherein these radicals defined for R₂are optionally substituted with at least one substituent selected fromhalogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals, said 1-piperazinyl radicals being optionallysubstituted at position 4 with an alkyl radical containing 1 to 4 carbonatoms or with a phenylalkyl radical in which the alkyl portion contains1 to 4 carbon atoms,cycloalkyl radicals containing 3 to 6 carbon atoms,cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals,cyano radicals, carboxyl radicals, and alkyloxycarbonyl radicals inwhich the alkyl portion contains 1 to 4 carbon atoms, wherein saidcycloalkyl, cycloalkenyl and bicycloalkyl radicals can be optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, or a phenyl radical optionally substituted with at least onesubstituent selected from halogen atoms and radicals selected from alkylradicals containing 1 to 4 carbon atoms and alkyloxy radicals containing1 to 4 carbon atoms, or a saturated or unsaturated nitrogenousheterocyclic radical containing 5 or 6 ring atoms and being optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, R₃ represents a hydrogen atom, an alkoxy radical containing 1 to4 carbon atoms, or an optionally substituted aryl radical, G₁ representsa group protecting the hydroxyl function, and G₂ represents an acetylradical or a group protecting the hydroxyl function, and (B) optionallydeprotecting at least one of the G₁ and G₂ -protected hydroxyl functionsof said product of formula (VIII), to obtain said product of formula(IX).
 36. A process for preparing a taxane derivative of formula (I):##STR30## in which R represents a hydrogen atom, an acetyl radical, or agroup protecting the hydroxyl function, and R₁ represents a benzoylradical or a radical R₂ --O--CO-- in which R₂ represents:an unbranchedor branched alkyl radical containing 1 to 8 carbon atoms, an alkenylradical containing 2 to 8 carbon atoms, an alkynyl radical containing 3to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, wherein these radicals definedfor R₂ are optionally substituted with at least one substituent selectedfrom halogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to4 carbon atoms, dialkylamino radicals in which each alkyl portioncontains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals, said 1-piperazinyl radicals being optionallysubstituted at position 4 with an alkyl radical containing 1 to 4 carbonatoms or with a phenylalkyl radical in which the alkyl portion contains1 to 4 carbon atoms, cycloalkyl radicals containing 3 to 6 carbon atoms,cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals,cyano radicals, carboxyl radicals, and alkyloxycarbonyl radicals inwhich the alkyl portion contains 1 to 4 carbon atoms, wherein saidcycloalkyl, cycloalkenyl and bicycloalkyl radicals can be optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, or a phenyl radical optionally substituted with at least onesubstituent selected from halogen atoms and radicals selected from alkylradicals containing 1 to 4 carbon atoms and alkyloxy radicals containing1 to 4 carbon atoms, or a saturated or unsaturated nitrogenousheterocyclic radical containing 5 or 6 ring atoms and being optionallysubstituted with at least one alkyl radical containing 1 to 4 carbonatoms, and Ar represents a phenyl or α- or β-naphthyl radical optionallysubstituted with at least one substituent selected from fluorine,chlorine, bromine, and iodine atoms and alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl,mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano and trifluoromethyl radicals, wherein the alkylradicals and alkyl portions of said above radicals independently contain1 to 4 carbon atoms, and the alkenyl and alkynyl radicals independentlycontain 3 to 8 carbon atoms and the aryl radicals and aryl portions ofsaid above radicals are independently selected from phenyl and α- andβ-naphthyl radicals, said process comprising the steps of: (A)esterifying a protected 10-deacetylbaccatin III or baccatin IIIderivative of formula (III): ##STR31## in which G₁ represents a groupprotecting the hydroxyl function and G₂ represents an acetyl radical ora group protecting the hydroxyl function, by means of an acid or salt offormula (VII): ##STR32## in which Ar and R₁ are defined as above and R₃represents a hydrogen atom, an alkoxy radical containing 1 to 4 carbonatoms, or an optionally substituted aryl radical, or by means of aderivative of said acid of formula (VII), to obtain a product of formula(VIII): ##STR33## in which Ar, R₁, R₃, G₁ and G₂ are defined as above,(B) deprotecting the side chain of said product of formula (VIII) (C)deprotecting the G₁ -protected hydroxyl function of said product offormula (VIII), and (D) optionally deprotecting the G₂ -protectedhydroxyl function of said product of formula (VIII), to obtain saidtaxane derivative of formula (I).